Recurrent pregnancy loss, experienced by 2-3% of couples who wish to have children, is becoming more common as women postpone pregnancy to later in their reproductive lives. There are few established causes of such loss and even fewer effective treatments. Recent reports suggest that highly skewed X inactivation (HSXI) is about threefold more common among women with recurrent abortion than among comparison samples. While these reports are provocative, all publications have been preliminary. Little is known about the karyotype of the losses associated with HSXI, information essential for understanding likely pathogenetic mechanisms. All studies are limited to women with recurrent losses, but the findings could also pertain to women with fewer losses. Comparison samples have also been largely those of convenience, without rigorous adjustment for maternal age. Two hypotheses have been proposed to explain an association of HSXI with recurrent loss. The first suggests that an X chromosomal defect leads both to HSXI and to loss of male conceptions. The second implicates maternal mosaicism as the cause of the HSXI and recurrent trisomy. We propose a third hypothesis: X-chromosomal defects lead both to HSXI and to an increase in trisomy due to premature ovarian aging. The primary goal of this study is to test this hypothesis. In addition we will explore associations with chromosomally normal male loss and examine whether associations with HSXI are limited to women with recurrent loss. We will study X inactivation skewing in 450 cases defined by the kaiyotype of an index spontaneous abortion, and a similar number of controls with an index live birth. Primary analyses will examine whether the proportion of HSXI differs between women with trisomic losses and controls: we will also examine HSXI in normal male losses, and test whether any association is confined to women with repeat losses. Lastly, we will investigate the mechanism of the observed HSXI by screening for X chromosome rearrangements, including microdeletions, in all women with HSXI. This may provide important leads for the identification of genes involved in ovarian maintenance.